Author + information
- Received August 17, 2017
- Revision received October 23, 2017
- Accepted November 16, 2017
- Published online January 17, 2018.
- Luisa Ciuffo, MDa,
- Susumu Tao, MD, PhDa,
- Esra Gucuk Ipek, MDa,
- Tarek Zghaib, MDa,
- Muhammad Balouch, MDa,
- Joao A.C. Lima, MDa,b,c,
- Saman Nazarian, MD, PhDd,
- David D. Spragg, MDa,
- Joseph E. Marine, MDa,
- Ronald D. Berger, MD, PhDa,e,
- Hugh Calkins, MDa and
- Hiroshi Ashikaga, MD, PhDa,∗ ()
- aDivision of Cardiology, Baltimore, Maryland
- bThe Russell H. Morgan Department of Radiology and Radiological Sciences, Baltimore, Maryland
- cDepartment of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Maryland
- dSection for Cardiac Electrophysiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
- eDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland
- ↵∗Address for correspondence:
Dr. Hiroshi Ashikaga, Cardiac Arrhythmia Service, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Carnegie 568, Baltimore, Maryland 21287.
Objectives The purpose of this study was to evaluate the usefulness of intra-atrial dyssynchrony as a marker of underlying left atrial (LA) remodeling to predict recurrence after the first atrial fibrillation (AF) ablation.
Background Catheter ablation for AF remains far from curative with relatively high recurrence rates. One of the causes of recurrence is poor patient selection out of a diverse patient population with different degrees of LA remodeling.
Methods We included 208 patients with a history of AF (59.4 ± 10 years of age; 26.0% nonparoxysmal AF) referred for catheter ablation of AF who underwent pre-ablation cardiac magnetic resonance in sinus rhythm. Clinical follow-up was 20 ± 6 months. Using tissue tracking cardiac magnetic resonance, we measured the LA longitudinal strain in each of 12 equal-length segments in 2- and 4-chamber views. We defined intra-atrial dyssynchrony as the standard deviation of the time to the peak longitudinal strain corrected by the cycle length (SD-time to peak strain [TPS], %).
Results Patients with AF recurrence after ablation (n = 101) had significantly higher SD-TPS than those without (n = 107; 3.9% vs. 2.2%; p < 0.001). Multivariable cox analysis showed that SD-TPS was associated with recurrence after adjusting for clinical risk factors, AF type, LA structure and function, and fibrosis (p < 0.001). Furthermore, receiver-operator characteristics analysis showed SD-TPS improved prediction of recurrence better than clinical risk factors, LA structure and function, and fibrosis.
Conclusions Intra-atrial dyssynchrony during sinus rhythm is an independent predictor of recurrence after the first catheter ablation of paroxysmal or persistent AF. Assessment of intra-atrial dyssynchrony may improve ablation outcomes by refining patient selection.
Atrial fibrillation (AF) is the most common arrhythmia in human beings, with the incidence increasing with the aging population (1). Catheter ablation involving pulmonary vein isolation is the cornerstone treatment for drug-refractory AF (2), but it is associated with a relatively high recurrence rate (2). One of the major causes of recurrence after ablation is poor patient selection out of a diverse patient population with different degrees of left atrial (LA) remodeling (2). Previous studies reported that indices associated with LA remodeling can predict AF recurrence after successful ablation, including the minimum left atrial volume (Vmin), LA emptying fraction (3), LA peak longitudinal strain, LA strain rate (3), and LA fibrosis (4). Recently, LA intra-atrial dyssynchrony assessed by 3-dimensional (3D) echocardiogram was also reported to predict AF recurrence in patients with paroxysmal AF (5). It is possible that intra-atrial dyssynchrony reflects the underlying LA remodeling and LA fibrosis better than the other indices regardless of AF type. In this study, we aimed to investigate the role of LA intra-atrial dyssynchrony during sinus rhythm in predicting the outcomes of ablation for both paroxysmal and persistent AF. We hypothesized that LA intra-atrial dyssynchrony of quantified by tissue tracking cardiac magnetic resonance (CMR) before catheter ablation predicts AF recurrence after the first AF ablation, independent of other indices of LA remodeling.
Consecutive patients with symptomatic, drug-refractory AF referred for catheter ablation of AF at the Johns Hopkins Hospital between June 2010 and December 2015 who underwent pre-procedural CMR were included. All patients undergoing AF ablation had pre-ablation imaging, either CMR or cardiac computed tomography. Approximately 50% to 70% of patients undergo CMR and the remaining 30% to 50% cardiac computed tomography. The decision to choose CMR over computed tomography is affected by several factors, including patient preference (e.g., claustrophobia), presence of pacemakers or defibrillators, physician preference, and scheduling logistics. Patients with prior AF ablation or surgical procedure in the LA were excluded. Patients who were in AF at the time of CMR were also excluded (n = 37). We also randomly divided our cohort into 2 groups, a training group (n = 103) and a test group (n = 105). The protocol was approved by the institutional review board and all the patients provided written informed consent.
CMR was performed with a 1.5-T scanner (Avanto, Siemens Medical Systems, Erlangen, Germany), a 6-channel phased array body coil in combination with a 6-channel spine matrix coil. Electrocardiogram (ECG)-gated, breath-holding cine CMR images were acquired in the long axis 2- and 4-chamber views by a true fast imaging with steady-state precession sequence with the following parameters: TE/TR 3.0/1.5 ms; flip angle 78°; in-plane pixel size 1.5 × 1.5 mm2; slice thickness 8 mm; slice spacing 2 mm; and 30 frames per ECG R-R interval with a temporal resolution of 20 to 40 ms. A fraction of patients also underwent respiratory-navigated, ECG-gated late gadolinium enhancement (LGE) to quantify LA fibrosis. LGE images were acquired within 15 to 25 min after the injection of gadopentetate dimeglumine (0.2 mmol/kg) (Bayer Healthcare Pharmaceuticals, Montville, New Jersey) using a fat-saturated 3D inversion recovery-prepared fast spoiled gradient-recalled echo sequence with the following parameters: TE/TR 1.52/3.8 ms; flip angle 10°; in-plane pixel size 1.3 × 1.3 mm2; and slice thickness 2.0 mm. The trigger time for 3D LGE images was optimized to acquire imaging data during LA diastole as determined by the cine CMR images. The optimal inversion time was determined by an inversion time scout scan (median 270 ms; range 240 to 290 ms) to maximize nulling of the LA myocardium. The endocardial and epicardial contours were manually draw around the LA myocardium (Figure 1). The image intensity ratio (6) was measured to quantify LA fibrosis using QMass MR version 7.2 (Leiden University Medical Center, Leiden, the Netherlands) on axial images from 3D axial image data (Figure 1). The image intensity ratio threshold of 1.22 that corresponds with a bipolar voltage 0.3 mV on intracardiac electrogram was used to define LA fibrosis (7).
Pulmonary vein isolation catheter ablation of AF was performed using an electroanatomic mapping system with an image integration module (CARTO and CartoMerge, Biosense Webster, Irvine, California) to merge pre-procedural CMR (8). The electrical isolation of the pulmonary veins were confirmed by a circular multipolar electrode mapping catheter (Lasso, Biosense Webster). In cases of persistent AF, the ablation procedure usually included additional ablation lesions (8). Ablation was performed with either an open-irrigated radiofrequency ablation catheter with or without force sensing, or a cryoballoon ablation catheter.
Recurrence of AF was defined as any episodes of AF, atrial flutter, or atrial tachycardia lasting more than 30 s after a 3-month blanking period (9). All medications, including antiarrhythmic and anticoagulation drugs, were continued in all patients during the blanking period. Patients were seen in clinic 10 to 12 weeks after ablation. At the clinic visit, antiarrhythmic and anticoagulation drugs were discontinued at the discretion of the physician according to patient’s stroke risk. Then, patients were followed by the referring physician on a regular basis. In addition, the patients received direct telephone interviews or emails with standardized questionnaire to report AF symptoms, if any. Patients were excluded if they were not followed for at least 6 months after ablation. When recurrence was suspected, patients underwent a 24-h Holter monitor or a 30-day event monitor depending on the symptom frequency.
LA dyssynchrony analysis
On cine CMR images, the LA endocardial and epicardial borders at the LA end diastole were defined by an operator with more than 3 years of experience in performing LA measurements by CMR, who was also blinded to the group assignment (Figure 2). The multimodality tissue tracking software version 6.1 (Toshiba, Japan) automatically divides the LA in 6 equilength segments in each of the 2- and 4-chamber views, creating a total of 12 segments (Figure 2). Longitudinal strain was calculated within each of the 12 segments (Figure 3). Based on those time series we defined the SD of the time to the peak longitudinal strain (time to peak strain [TPS]). We then corrected the SD-TPS by the cycle length to derive SD-TPS as a percentage of the cycle length:
The SD-TPS (%) quantifies the intra-atrial dyssynchrony of the LA reservoir function, and higher values reflect greater degrees of intra-atrial dyssynchrony.
Baseline patient demographics are presented as mean ± SD or percentage, and are compared using the Student t test, chi-square test, and Fisher exact test as appropriate. Multivariable Cox proportional hazards models were used to evaluate the effects of LA dyssynchrony on AF recurrence after ablation, and predictors that had a value of p < 0.25 in univariable analysis were included in multivariable models. Four models are presented: model 1, unadjusted; model 2, Adjusted for clinical characteristics (age, sex, type of AF, body mass index [BMI], history of heart failure, hypertension, and obstructive sleep apnea [OSA]); model 3, model 2 plus Vmin and maximum longitudinal LA strain (Smax); and model 4, model 3 plus percent LA fibrosis. Correlation between intra-atrial dyssynchrony (SD-TPS), maximum LA longitudinal strain (Smax) and percent LA fibrosis was defined by the Pearson correlation coefficient. Time-to-first recurrence is presented using Kaplan-Meier curves. A log-rank test was conducted to detect differences in the survival distributions for 2 curves, the 2 curves were generated based on receiver operating characteristic best cut point using the Liu’s criteria on the training group. The receiver operating characteristic curves were also generated to evaluate the additional value of intra-atrial dyssynchrony over LA structure and function in predicting AF recurrence. Comparison between the values of c-statistics was based on the method of DeLong et al. (10) In a subset of randomly selected patients (n = 15) intraobserver and interobserver reproducibility was performed, and the intraclass correlation coefficient (ICC) with a 2-way random model (ICC <0.40, poor; ICC >0.40 to 0.75, fair to good; and ICC >0.75, excellent agreement) was evaluated. The significance level of 0.05 was used for all hypothesis tests, and all t tests were 2-sided. The statistical computations were performed using STATA version 12.0 (StataCorp, College Station, Texas).
A total of 208 patients were included in the final analysis. Table 1 summarizes the patients’ clinical characteristics. There were 61 female patients (29.3%), and the average age was 59 ± 10 years (interquartile range: 51 to 66 years). A total of 101 patients (48.6%; recurrence group) developed recurrence after ablation. Compared with the AF-free group, the patients in the recurrence group were older (mean 61.1 vs. 57.1; p = 0.023), had a higher BMI (30.1 vs. 27.7; p = 0.002) and higher CHA2DS2 -VASC scores (1.9 vs. 1.3; p = 0.006) before ablation. Patients in the recurrence group were also more likely to have a history of hypertension, heart failure, OSA, and persistent AF than those in the AF-free group. Seventy percent of the patients (n = 146) included in the final analysis underwent respiratory-navigated, ECG-gated LGE to quantify LA fibrosis. Except for hypertension and calcium channel blockers use, which were higher in the training group, other clinical characteristics were similar between the training and test groups. Four of 101 patients (3.9%) in the recurrence group and 2 of 107 patients (1.9%) in the AF-free group underwent cardioversion within 3 to 4 weeks before CMR (p = 0.49). Acute pulmonary vein isolation was achieved in all patients.
Intra-atrial dyssynchrony, recurrence, and LA fibrosis
Of the 2,496 LA segments analyzed in a total of 208 patients, a total of 29 segments (1.2%) were excluded from the final analysis because they lacked well-defined peaks in the strain curves. Our results showed an excellent intrareader and inter-reader reproducibility, with an ICC of 0.86 for both indices, with respective mean difference of 0 and −0.05. Patients in the recurrence group had higher maximum and Vmin, lower total, passive and active LA emptying fraction, and lower strain and strain rates (Table 2). In addition, SD-TPS was significantly higher in the recurrence group than that of the AF-free group (3.9% vs. 2.2%; p < 0.001) (Table 2). The LA dyssynchrony analysis was performed in a consistent manner in all cases and took approximately 9 min per case. Figure 4 shows the relationship between intra-atrial dyssynchrony (SD-TPS [%], x-axis) and LA fibrosis (% total LA area). The correlation coefficient (r) between intra-atrial dyssynchrony and LA fibrosis was 0.34 (p < 0.001). The correlation coefficient between the maximum LA longitudinal strain and LA fibrosis was -0.21 (p = 0.004). All LA structure and function indices were similar between the training and test groups. The LA fibrosis analysis was also performed in a consistent manner in all cases and took approximately 30 min per case (4).
In model 1, a univariable (unadjusted) analysis identified age, BMI, AF type, history of heart failure, OSA, Vmin, Smax, and SD-TPS as a contributors of AF recurrence (Table 3). Patients with an SD-TPS of less than 2.86% had protective hazards for recurrence compared with an SD-TPS of 2.86% or greater (hazard ratio: 3.90; p < 0.001). After adjusting for age, sex, BMI, AF type, history of heart failure, OSA, hypertension, Vmin, and Smax, the SD-TPS remained significantly associated with higher hazards of recurrence (hazard ratio: 1.21; p < 0.001) (model 4 in Table 3).
Intra-atrial dyssynchrony predicts AF recurrence after ablation
We used the training group to define a cutoff of SD-TPS (<2.86% vs. >2.86%) based on the receiver operating characteristic curve, and applied the cutoff to the test group. We found that AF recurrence was significantly higher in patients with higher SD-TPS (p < 0.001) (Figure 5). Based on this result, we developed a modified CAAP-AF risk score (11) to incorporate SD-TPS in predicting recurrence after AF ablation: Coronary artery disease (+1 point), A [dyssynchrony (≥2.86: +2 point) or volume (≥37.6: +2 point)], Age (<50, 1; 50 to 60, +1 point; 60 to 70, +2 points; ≥70, +3 points), persistent or longstanding (+2 points), antiarrhythmic failed (none, 0; 1 to 2, +1 point; >2, +2 points), and sex category (female, +1 point). The modified CAAP-AF risk score showed a higher odds ratio (1.97 vs. 1.44) and a higher C-statistic (0.77 vs. 0.68; p = 0.024) compared with the original CAAP-AF risk score (Figure 6). Similarly, the specificity and positive predictive value of intra-atrial dyssynchrony were higher compared with other indices of LA structure and function (Table 4).
We found that intra-atrial dyssynchrony in pre-ablation CMR is an independent predictor of recurrence in patients referred for the first catheter ablation of AF, either paroxysmal or persistent.
Intra-atrial dyssynchrony as a marker of LA remodeling
Several lines of evidence suggest that intra-atrial dyssynchrony by echocardiography contributes indispensably to the mechanism of AF. For example, intra-atrial dyssynchrony is a strong predictor of new-onset AF in patients with heart failure (12). In addition, interatrial dyssynchrony predicts progression from paroxysmal to persistent AF (13). Furthermore, intra-atrial dyssynchrony predicts recurrence after catheter ablation of paroxysmal AF (5,14,15). To our knowledge, this is the first study to demonstrate intra-atrial dyssynchrony using CMR. The validation and reproducibility of LA tissue tracking CMR have been established (16). Compared with echocardiography, CMR is associated with higher in-plane spatial resolution and signal-to-noise ratio, which allows a better evaluation of thin LA walls (2 to 4 mm), particularly of the LA posterior wall where most of the fibrosis is localized.
Our findings suggest that intra-atrial dyssynchrony reflects the underlying LA remodeling independent of LA volume, similar to the extent of LA fibrosis detected by LGE (4) and LA function (3). In fact, our results suggest that intra-atrial dyssynchrony is a more specific marker of myocardial tissue scarring than LA fibrosis or LA function (Table 4). For example, although intra-atrial dyssynchrony was significantly associated with LA fibrosis (Figure 4), the AUC of intra-atrial dyssynchrony was significantly higher than that of LA fibrosis, whereas the AUC of LA function was not (Table 4). LA dyssynchrony also had a higher specificity. A possible explanation to account for these results is that intra-atrial dyssynchrony likely reflects subtle changes in atrial architecture that could generate AF, but are not captured by LGE. Of note, our LA strains in patients without recurrence were higher than those of our previous report (3). This finding likely reflects the current clinical practice to refer patients to catheter ablation in early stages of AF and LA remodeling. The possibility that cardioversion-induced atrial stunning could have confounded our findings is low because: 1) cardioversion was performed in only a minority of patients in both groups; 2) there was no significant difference in the fraction of patients who underwent cardioversion between both groups; and 3) CMR was performed on average 10 weeks after cardioversion, and cardioversion-induced atrial stunning usually recovers within 4 weeks (17).
Catheter ablation is superior to anti-arrhythmic drugs (18) in maintaining sinus rhythm, but remains far from curative, with recurrence rates of up to 40% (19). Intra-atrial dyssynchrony is a relatively simple method to quantify the degree of underlying LA remodeling to identify candidates who are responsive to catheter ablation. It helps to refine patient selection and, thus, reduce the recurrence by saving candidates with higher degrees of LA remodeling from potentially futile procedures and complications. Intra-atrial dyssynchrony can also be measured by a variety of imaging modalities, such as speckle-tracking echocardiography. The incorporation of intra-atrial dyssynchrony into routine clinical practice is relatively straightforward because it does not require extensive post-processing, unlike the quantification of LA fibrosis (6). In addition, the assessment of LA mechanical dyssynchrony is less time consuming than LA LGE.
This study represents a single-center analysis of patients referred for catheter ablation of AF. Therefore, there is a non-negligible chance of selection bias. Our definition of recurrence was strongly influenced by symptoms. Therefore, it is possible that we could have missed recurrence that is completely asymptomatic. For the dyssynchrony analysis, we used only 2- and 4-chamber cine CMR, which was included in a routine image acquisition protocol. Therefore, it is possible that our analysis underestimated the degree of dyssynchrony by missing regions that were not covered by those 2 views. Because the strain was 2-dimensional and was obtained only in the in-plane direction, SD-TPS may have been underestimated compared with those obtained from 3D strains. In addition, the CMR temporal resolution may also explain our lower values of dyssynchrony compared with those of 3D echocardiogram (20). Despite those potential causes of underestimation, our analysis demonstrated a significant association between intra-atrial dyssynchrony and AF recurrence. Therefore, we believe that the advantage of our approach outweighs the disadvantage of including more views to assess the whole LA deformation, which would increase the scan time and post-processing burden.
Intra-atrial dyssynchrony is an independent predictor of recurrence after catheter ablation of paroxysmal or persistent AF. Intra-atrial dyssynchrony is a relatively simple method to quantify the degree of underlying LA remodeling to identify candidates who are responsive to catheter ablation, and can refine patient selection and thus reduce the recurrence by saving candidates with higher degrees of LA remodeling from potentially futile procedures and complications.
COMPETENCY IN MEDICAL KNOWLEDGE: AF ablation is the indicated treatment for individuals with drug-refractory AF. However, the rate of recurrence after the procedure is relatively high, in part, due to poor patient selection before the intervention. Thus, identifying tools that assist the physician in the selection of adequate candidates is imperative. Our study examined the value of LA intra-atrial dyssynchrony in predicting the success of AF ablation beyond traditional risk factors, and other indices of LA structure and function.
TRANSLATIONAL OUTLOOK: Starting from present observations, further prospective studies are needed to determine the direct implications of this novel index of LA function—intra-atrial dyssynchrony—in the process of selecting the best candidates to be referred to AF ablation.
This work was supported by research grants from NIH/NHLBI R56 HL138429 (to Dr. Ashikaga), W.W. Smith Charitable Trust (to Dr. Ashikaga), Magic That Matters Fund for Cardiovascular Research (to Dr. Ashikaga), Zegar Family Foundation (to Dr. Ashikaga), Johns Hopkins University Institute of Clinical and Translational Research (to Dr. Ashikaga), the Edward St. John Foundation for AF Research (to Dr. Calkins), The Roz and Marvin H Weiner and Family Foundation (to Dr. Calkins), The Dr. Francis P. Chiaramonte Foundation (to Dr. Calkins), The Marilyn and Christian Poindexter Arrhythmia Research Fund (to Dr. Calkins), and The Norbert and Louise Grunwald Cardiac Arrhythmia Research Fund (to Dr. Calkins). Dr. Nazarian has received a research grant and served as a consultant for Biosense Weber; has served as the PI for national studies with St. Jude Medical; and has served as a consultant for CardioSolv and Siemens. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- atrial fibrillation
- body mass index
- cardiac magnetic resonance
- intraclass correlation coefficient
- left atrial
- late gadolinium enhancement
- obstructive sleep apnea
- maximum longitudinal LA strain
- time to peak strain
- minimum left atrial volume
- Received August 17, 2017.
- Revision received October 23, 2017.
- Accepted November 16, 2017.
- 2018 American College of Cardiology Foundation
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